ProjectSummary Despitetheenormouscomplexityofthebrain,itisbecomingincreasinglyapparentthatstructureslikethe cerebralcortexaremodular,relyingonasetofcanonicalcomputationsthatoccuracrossbrainregionsand modalitiestomediateperception,cognitionandbehavior.Oneimportantexampleofacanonicalcomputation isthesummationofvariousdriving,contextual,andmodulatoryneuronalinputstoyieldspikingoutput.The questionofhowcorticalnetworksintegratetheseinputsandtransformthemintospikingoutputsofindividual neuronsisofcentralimportancetoneuroscience.Asignificantchallengetounderstandingthesecomputations isthateachneuronisembeddedwithinalargercircuitofneurons,eachmodulatingoneanother?sactivity.So, understandinghowaparticularneuronrespondstoinputnecessarilyinvolvesunderstandingthelargercircuit. Recentoptogeneticstudieshavefounddifferentpatternsofinputsummationinmousevs.monkeyV1. Recentlydevelopedtheoreticalmodelshaveproducedspecificpredictionsaboutthedifferencesinnetwork circuitrythatcanleadtodifferencesinsummation,andpredicthowsummationnon-linearitiesdependon inputstothenetwork.Theproposedresearchwilltestthesepredictionsandseektounderstandthesecircuit computationsusingacombinationoftheoreticalworkandoptogeneticmodulationofcircuitsinmouseand monkey.Aim1:VaryingEandIoptogeneticstimulationandvisualcontrastindependentlytomeasure spikeresponsesummationtomultipleinputs.InthisAim,theoreticalmodelsofinputsummationacross varyingcorticalcircuitregimeswillbedeveloped,andrecentlydevelopedoptogenetictoolswillbeusedin awakemouseandmonkeyV1totestpredictionsgeneratedbythesemodelsandidentifythecorresponding regimes.Theoptogenetictoolsincludeanewviralstrategythatdirectsexpressionofdifferentopsinsto inhibitoryvs.excitatoryneocorticalneuronsinthemacaque.SimultaneousandindependentactivationofEand Iandthevisualstimulus,allwithinthistheoreticalframework,willenableustotestwhetherobserved differencesinsummationpropertiesreflectfundamentalspeciesdifferencesorreflectacommoncomputation operatingindifferentparameterregimes.Aim2:Determinethecircuitelementscontrollingdynamicsof corticalnetworkresponsesusingdynamicoptogeneticstimulation.InthisAim,experimentsusing dynamicoptogeneticandvisualstimulationpatternsandtheoreticalanalysisofthemodelswithdynamicinputs willbeusedtoelucidatethetemporaldynamicsofsummation.Aim3:Determineifdifferentinhibitory subclassescontroldifferentaspectsofinputintegration.Differentinhibitorysubclasseswillbestimulated optogeneticallytodeciphertheirrespectiverolesininputsummation.Takentogether,theseAimswillhelp definetherolesplayedbyexcitatoryandinhibitoryneuronsinmediatingsummationofneuronalinputstoyield spikingoutput.Thisinformationwillbecriticalforunderstandingbraindisordersassociatedwithfailuresin perceptionandattention,asisseenwithautism,schizophrenia,andAlzheimer?sdisease.